Hexamethylenetetramine: A powerful and novel inhibitor of gelation of deoxyhemoglobin S

The solubility of deoxyhemoglobin S increases markedly after exposure to hexamethylenetetramine. It has been determined that even at neutral pH hexamethylenetetramine undergoes a slow and slight decomposition into ammonia and formaldehyde. These decomposition products are shown to be responsible for the increase in the solubility of deoxyhemoglobin S. Formaldehyde cross-links the protein and ammonia increases the pH of the buffered hemoglobin solution. The hydrolysis equilibrium between HCHO, NH₃, and hexamethylenetetramine is shifted towards decomposition by the presence of hemoglobin and the reaction is facilitated by reducing agents. Red cells are shown to be readily permeable to hexamethylenetetramine and the potential of this relatively nontoxic chemical for sickle cell disease is discussed.